The purpose of this proposal is to develop, test, and apply new statistical design and analytical methodologies that can be used to identify low base rate drug - adverse event (AE) interactions. These new methods will then be applied to a wide range of existing non-experimental datasets to examine the relationship between SSRIs and suicide ideation, attempts, and completion. We have designed this research project as an integral collaboration between biostatisticians, research psychiatrists and clinicians, economists, and pharmacoepidemiologists, working with large ecological and electronic patient databases covering years where antidepressant use is varying dramatically. The first set of aims will lead to the development of new biostatistical methods for making inferences from spontaneous reporting and electronic medical record databases. Specifically, we will 1. develop new statistical designs and analyses for identifying drug-AE interactions using both spontaneous (SRS) and active reporting systems (ARS); 2. develop biostatistical methods to address selection and reporting bias in electronic medical record databases; 3. develop statistical methods for large-scale drug-AE screening. The second set of aims involves the critical application of these methods to existing large scale databases in order to examine the role of antidepressants in suicidality among different populations. The datasets range from the spontaneous reporting system (MedWatch), to electronic medical record databases (e.g., VA, PHARMetrics, Kaiser, and PHARMO, Indian Health Service), to the synthesis of information from randomized clinical trials (RCTs). The work in this proposal will be carried out by a research consortium that will study national and international drug safety issues. The multidisciplinary group includes the areas of statistics (Drs. Gibbons, (PI), Brown (co-Pi), Bhaumik, Duan, Hur, Marcus, SahaRay), psychiatry from adult, child, and genetic perspectives (Brent, Mann, Reynolds, Tsuang), health economics/econometrics (Meltzer, Heckman), pediatrics (Leslie), and pharmacoepidemiology (Valuck). Collaboration with members of the VA (Cunningham, Valenstein), Kaiser Permanente (Clarke, Gullion), PHARMO (Erkens) and the Indian Health Service (Perez) is an integral part of the proposal. [unreadable] [unreadable] [unreadable]